There has been considerable interest in research directed towards the development of animal models of Alzheimer's disease (AD). Most of these models have been designed to reproduce some features or symptoms of the disease. In non-transgenic models, disruption of specific neurotransmitter pathways has been used to mimic deficits in learning and memory. Furthermore, the development of a transgenic mouse model with all of the behavioral, neuropathological and biochemical features of AD has not yet been reported. Undoubtedly, the genetic background of the host mouse strain used to generate the transgenic lines plays an important role in developing the model system. Senescence-accelerated mice (SAM) have been characterized as strains of mice which undergo a natural, genetically controlled rapid advancement of aging. In particular, the SAMP8/Ta strain develop many of the neuropathological features, including neuronal loss and memory dysfunction, associated with accelerated aging and neurodegenerative diseases. Therefore, in order to study the role of betaAPP in the aging process, the ability to generate transgenic SAM strains overexpressing the human betaAPP695 and 751 isoforms specifically within neurons will be investigated and the transgenic SAM lines analyzed for the relationship between overexpression and neuronal physiology. The amount of betaAPP, at the transcriptional and translational levels, will be correlated with immunological analysis of the neuronal markers, synaptophysin and microtubule-associated protein-2. Overexpression of these genes on a genetically susceptible background of the SAMP8 strain should influence the aging process in a manner that will provide insights into the mechanisms operational in not only accelerated aging but also neurodegenerative diseases.